Synthesis of pseudopterosin compounds

Details Synthesis of pseudopterosin compounds Synthesis of pseudopterosin compounds

2001-06-27

2003-06-10

Barts, Samuel (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Silicon containing

C558S057000

Reexamination Certificate

active

06576781

ABSTRACT:

BACKGROUND OF THE INVENTION
The pseudopterosins are compounds produced by the Caribbean sea whip
Pseudopteragoria elisabethae
. These compounds are exemplified by the compounds pseudopterosin A and E which are remarkably active anti-inflammatory agents that were discovered by W. Fenical and collaborators.
In copending application Ser. No. 09/712,884 there is reported an especially simple and direct route for the synthesis of anti-inflammatory pseudopterosins such as pseudopterosin A (1) and pseudopterosin E (2) from inexpensive (S)-(−)-limonene.
1
The synthetic strategy used involved an aromatic annulation process to form the benzenoid ring and a cationic cyclization to generate the third ring of the aglycone intermediate 3.
2
An interesting discovery made in connection with the initial work was the finding that either the pseudopterosin A-F system or the C (1)-diastereomeric analogs could be accessed depending on the intermediate used for the cationic closure of the third ring. The present invention is directed to that discovery.
SUMMARY OF THE INVENTION
As shown in Scheme 1, ring closure of the mesylate 4 produced the pseudopterosin system (6), whereas cyclization of the corresponding tert-butyldimethylsilyl ether 5 afforded selectively the C (1)-diastereomeric product 7.
By exploiting the versatile acid-catalyzed cyclization of dienes such as 4 and 5, selective syntheses of both pseudopterosin G-J aglycone 15 and the potent cytotoxic agent helioporin E (16) have been accomplished as set forth herein. It is possible that the reported structure 18 for the related natural product pseudopteroxazole,
21
may also require revision in line with 15 and 16.
Surprisingly, these syntheses provided the first compelling evidence that these compounds are diastereomeric at C (1) relative to the pseudopterosins A-F, not at C (7) as originally reported. Thus, 15 and 16 best represents the stereochemical configurations of pseudopterosin G-J aglycone and helioporin E.
One preferred embodiment of the present invention is a new process for the synthesis of pseudopterosin compounds which has a number of advantages over previously known methods; including (1) an inexpensive chiral starting material (limonene), (2) the use of common or readily available reagents, (3) stereocontrol, (4) simplicity of execution, (5) good yields, and (6) directness. In addition, this synthesis illustrates a number of new and potentially widely useful synthetic methods of noteworthy aspects of stereocontrol and site selectivity.
The present invention is thus directed to the synthetic processes outlined in Schemes 1 2 and 3, to the novel intermediates recited therein, and to the uses of these compounds as synthetic precursors to the pseudopterosins. Other embodiments and aspects of the present invention include the novel synthetic procedures described herein, as detailed below.


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